Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

I. Cleynen; W. Engchuan; M.S. Hestand; T. Heung; A.M. Holleman; H.R. Johnston; T. Monfeuga; D.M. McDonald-McGinn; R.E. Gur; B.E. Morrow; A. Swillen; J.A.S. Vorstman; C.E. Bearden; E.W.C. Chow; M. van den Bree; B.S. Emanuel; J.R. Vermeesch; S.T. Warren; M.J. Owen; P. Chopra; D.J. Cutler; R. Duncan; A.V. Kotlar; J.G. Mulle; A.J. Voss; M.E. Zwick; A. Diacou; A. Golden; T.W. Guo; J.R. Lin; T. Wang; Z.D. Zhang; Y.J. Zhao; C. Marshall; D. Merico; A. Jin; B. Lilley; H.I. Salmons; O. Tran; P. Holmans; A. Pardinas; J.T.R. Walters; W. Demaerel; E. Boot; N.J. Butcher; G.A. Costain; C. Lowther; R. Evers; T.A.M.J. van Amelsvoort; E. van Duin; International 22q11.2 Brain and Behavior Consortium; Michael P. Epstein; Nigel M. Williams; Anne S. Bassett

doi:10.1038/s41380-020-0654-3

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

I. Cleynen, W. Engchuan, M.S. Hestand, T. Heung, A.M. Holleman, H.R. Johnston, T. Monfeuga, D.M. McDonald-McGinn, R.E. Gur, B.E. Morrow, A. Swillen, J.A.S. Vorstman, C.E. Bearden, E.W.C. Chow, M. van den Bree, B.S. Emanuel, J.R. Vermeesch, S.T. Warren, M.J. Owen, P. ChopraD.J. Cutler, R. Duncan, A.V. Kotlar, J.G. Mulle, A.J. Voss, M.E. Zwick, A. Diacou, A. Golden, T.W. Guo, J.R. Lin, T. Wang, Z.D. Zhang, Y.J. Zhao, C. Marshall, D. Merico, A. Jin, B. Lilley, H.I. Salmons, O. Tran, P. Holmans, A. Pardinas, J.T.R. Walters, W. Demaerel, E. Boot, N.J. Butcher, G.A. Costain, C. Lowther, R. Evers, T.A.M.J. van Amelsvoort, E. van Duin, International 22q11.2 Brain and Behavior Consortium, Michael P. Epstein^*, Nigel M. Williams^*, Anne S. Bassett^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the similar to 20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age >= 25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p(adj) = 6.73 x 10(-6)). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Original language	English
Pages (from-to)	4496-4510
Number of pages	15
Journal	Molecular Psychiatry
Volume	26
Issue number	8
Early online date	3 Feb 2020
DOIs	https://doi.org/10.1038/s41380-020-0654-3
Publication status	Published - Aug 2021

Keywords

ASSOCIATION
BEHAVIOR
BRAIN
CONSORTIUM
COPY-NUMBER VARIATION
DATABASE
INDIVIDUALS
MUTATIONS
PSYCHIATRIC-DISORDERS
VARIANTS

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Cleynen, I., Engchuan, W., Hestand, M. S., Heung, T., Holleman, A. M., Johnston, H. R., Monfeuga, T., McDonald-McGinn, D. M., Gur, R. E., Morrow, B. E., Swillen, A., Vorstman, J. A. S., Bearden, C. E., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., Warren, S. T., Owen, M. J., ... Bassett, A. S. (2021). Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Molecular Psychiatry, 26(8), 4496-4510. https://doi.org/10.1038/s41380-020-0654-3

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title = "Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion",

abstract = "Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the similar to 20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age >= 25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p(adj) = 6.73 x 10(-6)). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.",

keywords = "ASSOCIATION, BEHAVIOR, BRAIN, CONSORTIUM, COPY-NUMBER VARIATION, DATABASE, INDIVIDUALS, MUTATIONS, PSYCHIATRIC-DISORDERS, VARIANTS",

author = "I. Cleynen and W. Engchuan and M.S. Hestand and T. Heung and A.M. Holleman and H.R. Johnston and T. Monfeuga and D.M. McDonald-McGinn and R.E. Gur and B.E. Morrow and A. Swillen and J.A.S. Vorstman and C.E. Bearden and E.W.C. Chow and {van den Bree}, M. and B.S. Emanuel and J.R. Vermeesch and S.T. Warren and M.J. Owen and P. Chopra and D.J. Cutler and R. Duncan and A.V. Kotlar and J.G. Mulle and A.J. Voss and M.E. Zwick and A. Diacou and A. Golden and T.W. Guo and J.R. Lin and T. Wang and Z.D. Zhang and Y.J. Zhao and C. Marshall and D. Merico and A. Jin and B. Lilley and H.I. Salmons and O. Tran and P. Holmans and A. Pardinas and J.T.R. Walters and W. Demaerel and E. Boot and N.J. Butcher and G.A. Costain and C. Lowther and R. Evers and {van Amelsvoort}, T.A.M.J. and {van Duin}, E. and {International 22q11.2 Brain and Behavior Consortium} and Epstein, {Michael P.} and Williams, {Nigel M.} and Bassett, {Anne S.}",

year = "2021",

month = aug,

doi = "10.1038/s41380-020-0654-3",

language = "English",

volume = "26",

pages = "4496--4510",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer",

number = "8",

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Cleynen, I, Engchuan, W, Hestand, MS, Heung, T, Holleman, AM, Johnston, HR, Monfeuga, T, McDonald-McGinn, DM, Gur, RE, Morrow, BE, Swillen, A, Vorstman, JAS, Bearden, CE, Chow, EWC, van den Bree, M, Emanuel, BS, Vermeesch, JR, Warren, ST, Owen, MJ, Chopra, P, Cutler, DJ, Duncan, R, Kotlar, AV, Mulle, JG, Voss, AJ, Zwick, ME, Diacou, A, Golden, A, Guo, TW, Lin, JR, Wang, T, Zhang, ZD, Zhao, YJ, Marshall, C, Merico, D, Jin, A, Lilley, B, Salmons, HI, Tran, O, Holmans, P, Pardinas, A, Walters, JTR, Demaerel, W, Boot, E, Butcher, NJ, Costain, GA, Lowther, C, Evers, R, van Amelsvoort, TAMJ, van Duin, E, International 22q11.2 Brain and Behavior Consortium, Epstein, MP, Williams, NM & Bassett, AS 2021, 'Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion', Molecular Psychiatry, vol. 26, no. 8, pp. 4496-4510. https://doi.org/10.1038/s41380-020-0654-3

TY - JOUR

T1 - Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

AU - Cleynen, I.

AU - Engchuan, W.

AU - Hestand, M.S.

AU - Heung, T.

AU - Holleman, A.M.

AU - Johnston, H.R.

AU - Monfeuga, T.

AU - McDonald-McGinn, D.M.

AU - Gur, R.E.

AU - Morrow, B.E.

AU - Swillen, A.

AU - Vorstman, J.A.S.

AU - Bearden, C.E.

AU - Chow, E.W.C.

AU - van den Bree, M.

AU - Emanuel, B.S.

AU - Vermeesch, J.R.

AU - Warren, S.T.

AU - Owen, M.J.

AU - Chopra, P.

AU - Cutler, D.J.

AU - Duncan, R.

AU - Kotlar, A.V.

AU - Mulle, J.G.

AU - Voss, A.J.

AU - Zwick, M.E.

AU - Diacou, A.

AU - Golden, A.

AU - Guo, T.W.

AU - Lin, J.R.

AU - Wang, T.

AU - Zhang, Z.D.

AU - Zhao, Y.J.

AU - Marshall, C.

AU - Merico, D.

AU - Jin, A.

AU - Lilley, B.

AU - Salmons, H.I.

AU - Tran, O.

AU - Holmans, P.

AU - Pardinas, A.

AU - Walters, J.T.R.

AU - Demaerel, W.

AU - Boot, E.

AU - Butcher, N.J.

AU - Costain, G.A.

AU - Lowther, C.

AU - Evers, R.

AU - van Amelsvoort, T.A.M.J.

AU - van Duin, E.

AU - International 22q11.2 Brain and Behavior Consortium

AU - Epstein, Michael P.

AU - Williams, Nigel M.

AU - Bassett, Anne S.

PY - 2021/8

Y1 - 2021/8

N2 - Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the similar to 20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age >= 25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p(adj) = 6.73 x 10(-6)). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

AB - Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the similar to 20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age >= 25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p(adj) = 6.73 x 10(-6)). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

KW - ASSOCIATION

KW - BEHAVIOR

KW - BRAIN

KW - CONSORTIUM

KW - COPY-NUMBER VARIATION

KW - DATABASE

KW - INDIVIDUALS

KW - MUTATIONS

KW - PSYCHIATRIC-DISORDERS

KW - VARIANTS

U2 - 10.1038/s41380-020-0654-3

DO - 10.1038/s41380-020-0654-3

M3 - Article

C2 - 32015465

SN - 1359-4184

VL - 26

SP - 4496

EP - 4510

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 8

ER -

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Abstract

Keywords

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